EA025194B1 - Semisolid aqueous pharmaceutical composition containing tapentadol - Google Patents

Abstract

The present invention relates to a semisolid aqueous pharmaceutical composition for topical and/or local administration containing tapentadol or a physiologically acceptable salt thereof, wherein the pH value of the aqueous phase of the composition is at least 5.5. The present invention provides such a semisolid pharmaceutical composition of tapentadol which have advantages over the pharmaceutical compositions of the prior art.

Description

The invention relates to a semi-solid pharmaceutical composition based on water, containing tapentadol or a physiologically acceptable salt thereof.

Tapentadol is a centrally acting analgesic with a double mechanism of action as an agonist of the μ opioid receptor and as an inhibitor of norepinephrine reuptake (see T.M. T / ccNcSxx et al., Igidk 1bf GShigs. 2006, 12, 1053-1061. ) Solid oral dosage forms of tapentadol are known from the prior art, for example from νθ 02/67651, νθ 03/035053, νθ 2006/002886, νθ 2007/128412, νθ 2007/128413, νθ 2008/110323, νθ 2009/092601, νθ 2009/067703, as well as I82010-272815. νθ 2008/110323, which discloses a composition for parenteral administration, consisting of 20 g of (1K, 2K) -3- (3-dimethylamino-1-ethyl-2methylpropyl) phenol hydrochloride in 1 L of water for injection purposes, which has been isotonized by the addition of IA1.

However, solid oral dosage forms containing tapentadol are not satisfactory in all respects, and there is a need for pharmaceutical dosage forms that have advantages over known solid oral dosage forms.

For example, pain can be caused by local exposure, which does not require systemic treatment. In this case, systemic side effects can be avoided if tapentadol is applied topically and / or locally. Traditionally, the drug can be applied directly to the source of pain in a high dose, thus keeping the load on the whole body to a minimum. As a consequence, there is a need for pharmaceutical dosage forms containing tapentadol for topical and / or local use.

The stability of the active substance in the final product is the main task for the compiler of drug formulations. Generally, drug substances are less stable in the aquatic environment than solid dosage forms, and it is also important to properly stabilize and preserve water-based liquid dosage forms, such as solutions, suspensions, and emulsions. In these products, acid-base reactions, acid or base catalysis, oxidation, and reduction can occur. These reactions can occur due to interactions between the active substance and the ingredients, interactions between the ingredients or interactions between the container and the product. For pH-sensitive compounds, any of these interactions can change the pH and can cause precipitation.

Oxidizing unstable active substances or vitamins, essential oils, as well as almost all fats and oils can be oxidized as a result of self-oxidation. Such reactions can be caused by heat, light, peroxides, or other unstable compounds or heavy metals such as copper or iron.

The effects of metal traces can be minimized by the use of chelating agents such as EDTA. Antioxidants can slow down or delay oxidation by quickly reacting with free radicals as soon as they form (suppression). Common antioxidants include propyl, octyl, and gallic acid dodecyl esters, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, sodium ascorbate, monothioglycerol, potassium or sodium metabisulfite, propionic acid, sodium propyl sulfate, bis propyl sulfite, bis propyl sulfite, bis propyl sulfate, sodium bisulfate, also tocopherols or vitamin E.

In addition to stabilizing pharmaceuticals from chemical and physical degradation, liquid and semi-solid preparations, especially those for repeated use, should usually be protected from microbial contamination. Unlike solid preparations, aqueous solutions, syrups, emulsions, as well as suspensions often provide an excellent growth medium for microorganisms such as mold, yeast, and bacteria (for example, Rkeyoshopak Aegldshoka, E. Soi, 8a1topa11a 8 pp. SapbMa a1Ysap8, Azregd Shiz Shdeg). Contamination with these microorganisms can occur during manufacture or when a dose is taken from a multiple-dose dosage form. The growth of microorganisms occurs when a sufficient amount of water is present in the dosage form. Two-phase oil-water systems are particularly prone to be an excellent breeding ground for microorganisms.

Ophthalmic and injection preparations are traditionally sterilized by autoclaving or by filtration. However, many of them require the presence of an antimicrobial preservative in order to maintain sterile conditions throughout their indicated shelf life, in particular with regard to reusable preparations.

When a preservative is required, its choice is based on several factors that need to be taken into account, in particular, the choice depends on the place of application, whether it is internal, external or ophthalmic application (for more information, refer to, for example, Keshtop, Tie 8aepse apb Prgase oG Ragshasu, 21st ed., Irrsoy Ulap & \ νί11 <ίηδ „2005).

Many liquid and semi-solid dosage forms, especially dosage forms for

- 1 025194 repeated use and / or dosage forms based on oil-water, contain parabens as preservatives, for example methylparaben (methyl-4-hydroxybenzoate) and propyl paraben (propyl-4hydroxybenzoate). For example, in the Federal Republic of Germany, semi-solid dosage forms containing analgesics, such as ibuprofen and parabens, are marketed under the trademarks: Ωοίβίΐ®. 1Lyur® and Elasig®.

Due to the many adjuvants and additives in pharmaceutical dosage forms, it is recommended that all ingredients be listed on containers in order to reduce the risks that hypersensitive patients face when using these products.

Other commercially available pharmaceutical dosage forms contain sorbic acid or a potassium salt thereof (e.g., Moib! ®) or benzalkonium chloride as a preservative. Recently, side effects resulting from mucosal damage caused by benzalkonium chloride and potassium sorbate have been noted (see S.U. But et al., At 1 Ρΐιίηοΐ. 2008, 22 (2), 125-9). Since hypersensitive reactions to preservatives in local ophthalmic therapy are described, quaternary ammonium (benzalkonium chloride) is mainly associated with toxic irritant reactions, while organo-mercury compounds (thimerosal) and alcohols (chlorobutanol) are highly correlated with allergic reactions (see 1. Nopd et al., Sigg Θρίη A11eg§u S1sh 1tipo1. 2009, 9 (5), 447-53). Parabens are involved in many cases of sensitivity resulting from contact associated with skin contact (see M.S. δοηί et al., Άοοά Сет етοχχοΐ. 2001, 39 (6), 513-32), and it was noted that they cause a weak estrogenic activity (see δ. Οίίάιί. Ροοά Siet Τοχκοΐ. 2002, 40 (12), 1807-13 and M.S. δοηί et al., Ροοά Siet Τοχκοΐ. 2005, 43 (7), 985-015).

Due to these undesirable side effects of known preservatives, it is desirable to provide pharmaceutical compositions for topical and / or local application that exhibit a sufficient shelf life in the absence of preservatives, or at least in the presence of relatively low amounts thereof.

The objective of the invention is to provide pharmaceutical dosage forms of tapentadol, which have advantages over pharmaceutical dosage forms of the prior art. Pharmaceutical dosage forms should not have the above side effects based on preservatives, as is traditionally the case with pharmaceutical dosage forms containing preservatives, such as allergic reactions, and should be suitable for topical and / or local use of tapentadol.

The specified task was achieved using the object expressed in the claims.

It was unexpectedly found that tapentadol as such demonstrates preservative properties and, therefore, when composing relatively unstable compositions, in particular aqueous liquid or semi-solid compositions, preservatives can be completely eliminated or, at least, the need for their presence is relatively low quantities in order to reach the indicated expiration date.

The drawing shows the viscosity curves of the compositions in accordance with the invention 1-1 and 1-2, installed at a temperature of 25 ° C using a rotational viscometer.

A first aspect of the invention relates to a semi-solid, water-based pharmaceutical composition containing tapentadol.

The term pharmaceutical composition includes any pharmaceutical preparation or dosage form that is adapted for administration to a human or animal.

For the purposes of description, the term tapentadol includes the free base ((1K, 2K) -3- (3dimethylamino-1-ethyl-2-methylpropyl) phenol), as well as any physiologically acceptable salt thereof, in particular hydrochloride ((1K, 2K ) -3- (3-dimethylamino-1-ethyl-2-methylpropyl) phenol hydrochloride). Thus, unless expressly stated otherwise, the term tapentadol refers not only to the free base, but also to any physiologically acceptable salt. In addition, unless expressly stated otherwise, all amounts, composition and concentrations are equivalents that relate to tapentadol in the form of a free base.

In a preferred embodiment, the content of tapentadol is in the range from 0.01 to 50 wt.%, More preferably in the range of 0.05-45 wt.%, Even more preferably 0.1-40 wt.%, Even further more preferably 0, 5-35 wt.%, Most preferably 1.0-30 wt.%, In particular 5.0-25 wt.% Based on the total weight of the composition.

In another preferred embodiment, the content of tapentadol is in the range from 0.0001 to 5.0 wt.%, More preferably in the range of 0.0005-4.5 wt.%, Even more preferably 0.001-4.0 wt.%, Still further more preferably 0.005-3.5 wt.%, most preferably 0.01-3.0 wt.% and, in particular, in the range of 0.05-2.5 wt.% based on the total weight of the composition. In a preferred embodiment, the content of tapentadol is in the range from 0.01 to 3.0 wt.%, More preferably in the range of 0.05-2.8 wt.%, Even more preferably 0.1-2.6 wt.%, still further more preferably 0.2-2.4 wt.%, most preferably in the range of 0.3-2.2

- 2 025194 wt.% And, in particular, in the range of 0.4-2.0 wt.% Based on the total weight of the composition.

Preferably, the content of tapentadol is equal to or lower than 5.0 wt.% Based on the total weight of the composition.

In a preferred embodiment, the content of tapentadol is in the range of 0.4 ± 0.35 wt.%, More preferably 0.4 ± 0.3 wt.%, Even more preferably 0.4 ± 0.2 wt.%, Still further more preferably 0.4 ± 0.15 wt.%, most preferably 0.4 ± 0.1 wt.%, and in particular 0.4 ± 0.05 wt.% based on the total weight of the composition.

In another preferred embodiment, the content of tapentadol is in the range of 0.6 ± 0.5 wt.%, More preferably 0.6 ± 0.4 wt.%, Even more preferably 0.6 ± 0.3 wt.%, still further more preferably 0.6 ± 0.2 wt.%, most preferably 0.6 ± 0.1 wt.%, and in particular 0.6 ± 0.05 wt.% based on the total weight of the composition.

In yet another preferred embodiment, the content of tapentadol is in the range of 0.8 ± 0.6 wt.%, More preferably 0.8 ± 0.5 wt.%, Even more preferably 0.8 ± 0.4 wt.% , even further more preferably 0.8 ± 0.3 wt.%, most preferably 0.8 ± 0.2 wt.%, and in particular 0.8 ± 0.1 wt.% based on the total weight of the composition .

In yet another preferred embodiment, the content of tapentadol is in the range of 1.0 ± 0.9 wt.%, More preferably 1.0 ± 0.7 wt.%, Even more preferably 1.0 ± 0.5 wt. %, still further more preferably 1.0 ± 0.3 wt.%, most preferably 1.0 ± 0.2 wt.%, and in particular 1.0 ± 0.1 wt.% based on the total weight composition.

In a further preferred embodiment, the content of tapentadol is in the range of 1.2 ± 1.0 wt.%, More preferably 1.2 ± 0.8 wt.%, Even more preferably 1.2 ± 0.6 wt.%, still further more preferably 1.2 ± 0.4 wt.%, most preferably 1.2 ± 0.2 wt.%, and also, in particular, 1.2 ± 0.1 wt.% based on the total weight of the composition.

In a preferred embodiment, the content of tapentadol is at least 0.05, at least 0.10 or at least 0.15 wt.%, More preferably at least 0.20, at least 0.25 or at least 0.30 wt.%, Even more preferably at least 0.35, at least 0.40 or at least 0.45 wt.%, Even further more preferably at least 0.50, at least 0, 55 or at least 0.60 wt.%, Most preferably at least 0.65, at least 0.70 or at least 0.75 wt.%, And, in particular, at least 0.80, at least 0.85, or at least 0.90 wt.% based on the total weight of the composition.

Preferably, tapentadol is uniformly distributed in the composition in accordance with the invention. The content of tapentadol of two parts of the composition, having a volume of 0.1 ml each, differs from each other, preferably no more than ± 10%, more preferably no more than ± 7.5%, even more preferably no more than ± 5 , 0%, most preferably not more than ± 2.5%, and also, in particular, not more than ± 1.0%.

Preferably, the composition in accordance with the invention is characterized by a relatively uniform density distribution. Preferably, the density of two parts of the pharmaceutical composition having a volume of 0.1 ml each differs from each other by no more than ± 10%, more preferably not more than more than ± 7.5%, even more preferably not more than ± 5.0%, most preferably not more than ± 2.5%, and in particular not more than ± 1.0%.

The composition in accordance with the invention is a water-based composition. For the purposes of description, the term water-based means that its water content is preferably higher than the usual water content in solid pharmaceutical compositions in which the moisture content increases due to atmospheric influence, due to the more or less pronounced hygroscopicity of their components.

Preferably, the water content of the composition is at least 0.5 wt.%, More preferably at least 1.0 wt.%, Even more preferably at least 2.0 wt.%, Even further more preferably at least 3.0 wt.%, most preferably at least 4.0 wt.% and, in particular, at least 5.0 wt.% based on the total weight of the composition.

In a preferred embodiment, the water content of the composition is in the range of 35 ± 30 wt.%, More preferably 35 ± 25 wt.%, Even more preferably 35 ± 20 wt.%, Even further more preferably 35 ± 15 wt.%, most preferably 35 ± 10 wt.% and, in particular, 35 ± 5 wt.% based on the total weight of the composition.

In another preferred embodiment, the water content of the composition is in the range of 45 ± 30 wt.%, More preferably 45 ± 25 wt.%, Even more preferably 45 ± 20 wt.%, Even more preferably 45 ± 15 wt.%, most preferably 45 ± 10 wt.% and, in particular, 45 ± 5 wt.% based on the total weight of the composition.

In yet another preferred embodiment, the water content of the composition is in the range of 55 ± 30 wt.%, More preferably 55 ± 25 wt.%, Even more preferably 3,025194 but 55 ± 20 wt.%, Even further more preferably 55 ± 15 wt.%, Most preferably 55 ± 10 wt.% And, in particular, 55 ± 5 wt.% Based on the total weight of the composition.

In yet another preferred embodiment, the water content of the composition is in the range of 65 ± 30 wt.%, More preferably 65 ± 25 wt.%, Even more preferably 65 ± 20 wt.%, Even further more preferably 65 ± 15 wt. %, most preferably 65 ± 10 wt.% and, in particular, 65 ± 5 wt.% based on the total weight of the composition.

The pharmaceutical composition according to the invention is semi-solid at room temperature. One skilled in the art knows how to distinguish semi-solid pharmaceutical compositions from solid pharmaceutical compositions, as well as from liquid pharmaceutical compositions. The term semi-solid is common in the art. For the purpose of description, the term semi-solid preferably has the meaning as used in the European Pharmacopoeia.

Preferably, the semi-solid preparation becomes liquid at a temperature which is at most 100 ° C, more preferably which is at most 95 ° C, even more preferably which is at most 90 ° C, even further more preferably which is at most 85 ° C, most preferably which is at most 80 ° C, in particular which is at most 75 ° C.

In accordance with the European Pharmacopoeia, semi-solid preparations can be systemically divided into ointments (hydrophobic, hydrophilic and absorbent ointments), creams (hydrophobic and hydrophilic), gels (hydrophobic and hydrophilic), pastes, lotions and plasters. Thus, the composition in accordance with the invention is preferably selected from the group consisting of ointments, creams, gels, pastes, lotions and plasters.

Ointments are semi-solid lipid-based preparations that do not necessarily contain an aqueous phase and are homogeneous. In a simplified form, they are characterized as single-phase preparations, despite the fact that liquid and / or solid particles can be dispersed in them. Typical base dosage forms for hydrophobic ointments include hard paraffin, soft paraffin, vegetable oils, animal fats, hydrogenated oils, oil-based synthetic materials, partially synthetic glycerides and / or waxes. Hydrophobic ointments can only absorb a small amount of water. Hydrophilic ointments and absorbent ointments additionally contain emulsifying substances that increase their activity in water absorption. Hydrophilic ointments are based on dosage forms that are soluble in water. They often contain polyethylene glycol.

Creams are biphasic or multiphase systems that contain an aqueous and lipid phase. They often have an opaque appearance, as opposed to translucent ointments. Creams contain at least one surfactant (emulsifying agent) whose hydrophilicity determines whether the cream is hydrophobic (e.g., water-oil type), hydrophilic (e.g., oil-water type), or both. The characteristics of the cream phase are often complex. For example, creams may contain more phases than just the aqueous and lipid phases, for example, the aqueous phase and two lipid phases. Either they may additionally contain solid particles, or the lipid phase may be solid in itself. For this reason, creams are not usually classified as emulsions. They may, however, be referred to as emulsoids.

Gels are semi-solid systems in which a liquid solidifies with a gelling agent, which forms a three-dimensional cross-linked network inside the liquid. The fluid may be water based (hydrophobic gel, oleogel) or lipid based (hydrophilic gel, hydrogel). Gels traditionally do not show fluidity when in a steady state.

Creams and ointments may also contain thickening agents, and their classification is not unique in every case. For example, there are semi-solid systems that can be classified as either oil-in-water creams or hydrogels, and are thus also referred to as emulsion gels.

Pastes are lipid-based preparations that contain a large amount of solid particles dispersed in them. They usually contain only a small amount of water. Drugs of this type that contain large amounts of water are commonly referred to as lotions.

In common parlance, liquefied aqueous multiphase preparations, which are suspensions of solid particles in hydrophilic solvents or emulsions, are also referred to as lotions.

Preferably, the composition of the invention is selected from the group consisting of ointments, creams, liquid ointments, gels, emulsions, suspensions, lotions, liniment, pastes, lotions, suspension gels and emulsion gels.

In a preferred embodiment, the composition according to the invention is an emulsion preparation, such as a cream or lotion.

The emulsoid preparation may be hydrophilic, hydrophobic or amphiphilic.

- 4 025194

For the purposes of the description, the term hydrophilic emulsion preparation refers to any emulsion preparation in which the aqueous phase is an external phase that includes two-phase water-oil preparations and multi-phase water-oil-water preparations.

For the purposes of the description, the term hydrophobic emulsion preparation refers to any biphasic emulsion preparation in which the lipid phase represents an external phase that includes biphasic oil-water preparations.

Preferably, the emulsion preparation is hydrophilic. In particular, an emulsion preparation is an oil-water (oil-in-water) type or a water-oil-water type (an emulsion preparation water-oil-in-water).

In another preferred embodiment, the composition in accordance with the invention is a suspension preparation, preferably selected from the group consisting of sustained release suspensions, gels and liquid ointments, as well as lotions.

In a preferred embodiment, the water-based composition in accordance with the invention is a single phase dosage form. In another preferred embodiment, the composition in accordance with the invention is a biphasic or multiphase dosage form.

Preferably, the composition comprises at least one aqueous phase and at least one lipid phase.

In a preferred embodiment, the aqueous phase and the lipid phase form a bicoherent system.

In another preferred embodiment, the aqueous phase and the lipid phase form an emulsoid or suspendoid system in which they can independently be represented as a dispersed phase and / or coherent phase.

In the case where the emulsoid system contains a solid phase, two or three coherent phases may be present. For example, the lipid phase may be dispersed in the aqueous phase and comprise a second aqueous phase dispersed therein (such as water-oil-water).

Preferably, the emulsion system comprises at least one aqueous coherent phase.

The semi-solid, water-based pharmaceutical composition according to the invention contains tapentadol.

Preferably, tapentadol is dispersed in the composition. In particular, tapentadol is dissolved in the aqueous phase, which can either represent the single phase of the composition or be part of a multiphase system.

In a preferred embodiment, the aqueous phase of the composition has a pH of at least 5.50, more preferably at least 5.75, even more preferably at least 6.00, even further more preferably at least 6.25, even more preferably at least 6.50, most preferably at least 6.75, and in particular at least 7.00.

In a preferred embodiment, the pH of the aqueous phase of the composition is at least 5.4, more preferably at least 5.5, even more preferably at least 5.6, even further more preferably at least 5.7, most preferably at least 5.8, in particular at least least 5.9.

Preferably, the pH is in the range from 5.4 to 6.5, more preferably 5.5 to 6.3, even more preferably 5.4-6.0.

In a preferred embodiment, the pH is in the range of 5.7 ± 0.3, more preferably 5.7 ± 0.25, even more preferably 5.7 ± 0.2, most preferably 5.7 ± 0.15, and in particular 5.7 ± 0.1.

In a preferred embodiment, the pH is in the range of 6.0 ± 0.6, more preferably 6.0 ± 0.5, even more preferably 6.0 ± 0.4, even more preferably 6.0 ± 0.3, most preferably 6.0 ± 0.2, and in particular 6.0 ± 0.1 .

In a preferred embodiment, the pH is in the range of 6.5 ± 1.0, more preferably 6.5 ± 0.9, even more preferably 6.5 ± 0.8, even further more preferably 6.5 ± 0.7, even more preferably 6.5 ± 0.6 or 6.5 ± 0.5, most preferably 6.5 ± 0.4 or 6.5 ± 0.3, as well as, in particular, 6.5 ± 0.2 or 6.5 ± 0.1.

In a preferred embodiment, the pH is within the range of 7.0 ± 1.4 or 7.0 ± 1.3, more preferably 7.0 ± 1.2 or 7.0 ± 1.1, even more preferably 7.0 ± 1.0 or 7.0 ± 0.9, even more preferably 7.0 ± 0.8 or 7.0 ± 0.7, even more preferably 7.0 ± 0.6 or 7.0 ± 0.5, most preferably 7.0 ± 0.4 or 7.0 ± 0.3, and in particular 7.0 ± 0.2 or 7.0 ± 0.1.

In a preferred embodiment, the pH is in the range of 7.5 ± 1.4 or 7.5 ± 1.3, more preferably 7.5 ± 1.2 or 7.5 ± 1.1, even more preferably 7.5 ± 1.0 or

- 5,025194

7.5 ± 0.9, even further more preferably 7.5 ± 0.8 or 7.5 ± 0.7, even more preferably 7.5 ± 0.6 or 7.5 ± 0.5, most preferably 7.5 ± 0.4 or 7.5 ± 0.3, and in particular 7.5 ± 0.2 or 7.5 ± 0.1 .

In a preferred embodiment, the pH is within the range of 8.0 ± 1.4 or 8.0 ± 1.3, more preferably 8.0 ± 1.2 or 8.0 ± 1.1, even more preferably 8.0 ± 1.0 or 8.0 ± 0.9, even more preferably 8.0 ± 0.8 or 8.0 ± 0.7, even more preferably 8.0 ± 0.6 or 8.0 ± 0.5, most preferably 8.0 ± 0.4 or 8.0 ± 0.3, and in particular 8.0 ± 0.2 or 8.0 ± 0.1.

In a preferred embodiment, the pH is in the range of 8.5 ± 1.4 or 8.5 ± 1.3, more preferably 8.5 ± 1.2 or 8.5 ± 1.1, even more preferably 8.5 ± 1.0 or 8.5 ± 0.9, even further more preferably 8.5 ± 0.8 or 8.5 ± 0.7, even more preferably 8.5 ± 0.6 or 8.5 ± 0.5, most preferably 8.5 ± 0.4 or 8.5 ± 0.3, and in particular 8.5 ± 0.2 or 8.5 ± 0.1.

Surprisingly, tapentadol has been shown to exhibit a pH-dependent antimicrobial effect. Thus, the pH of the aqueous phase of the composition in accordance with the invention is preferably adjusted to a value within the physiologically acceptable limit where the antimicrobial effect of tapentadol is maximal.

In a preferred embodiment, the concentration of tapentadol is equal to or lower than 20 mg / ml based on the total volume of all aqueous phases within the composition.

In a preferred embodiment, the concentration of tapentadol is in the range of 17.5 ± 6 mg / ml, more preferably 17.5 ± 5 mg / ml, even more preferably 17.5 ± 4 mg / ml, even more preferably 17.5 ± 3 mg / ml, most preferably 17.5 ± 2 mg / ml, and in particular 17.5 ± 1 mg / ml, based on the total volume of all aqueous phases within the composition.

In another preferred embodiment, the concentration of tapentadol is in the range of 15 ± 6 mg / ml, more preferably 15 ± 5 mg / ml, even more preferably 15 ± 4 mg / ml, even more preferably 15 ± 3 mg / ml, most preferably 15 ± 2 mg / ml, and in particular 15 ± 1 mg / ml, based on the total volume of all aqueous phases within the composition.

In yet another preferred embodiment, the concentration of tapentadol is in the range of 12.5 ± 6 mg / ml, more preferably 12.5 ± 5 mg / ml, even more preferably 12.5 ± 4 mg / ml, even further more preferably 12 5 ± 3 mg / ml, most preferably 12.5 ± 2 mg / ml, and in particular 12.5 ± 1 mg / ml, based on the total volume of all aqueous phases within the composition.

In yet another preferred embodiment, the concentration of tapentadol is in the range of 10 ± 6 mg / ml, more preferably 10 ± 5 mg / ml, even more preferably 10 ± 4 mg / ml, even more preferably 10 ± 3 mg / ml, most preferably 10 ± 2 mg / ml, and in particular 10 ± 1 mg / ml based on the total volume of all aqueous phases within the composition.

In yet another preferred embodiment, the concentration of tapentadol is in the range of 7.5 ± 6 mg / ml, more preferably 7.5 ± 5 mg / ml, even more preferably 7.5 ± 4 mg / ml, even further more preferably 7.5 ± 3 mg / ml, most preferably 7.5 ± 2 mg / ml, and in particular 7.5 ± 1 mg / ml based on the total volume of all aqueous phases within the composition.

In a further preferred embodiment, the concentration of tapentadol is in the range of 4 ± 3 mg / ml, more preferably 4 ± 2.5 mg / ml, even more preferably 4 ± 2 mg / ml, even further more preferably 4 ± 1.5 mg / ml, most preferably 0.6 ± 1 mg / ml, and in particular 0.6 ± 0.05 mg / ml, based on the total volume of all aqueous phases within the composition.

In another preferred embodiment, the concentration of tapentadol is equal to or higher than 20 mg / ml based on the total volume of all aqueous phases within the composition.

In a preferred embodiment, the concentration of tapentadol is in the range of 22.5 ± 6 mg / ml, more preferably 22.5 ± 5 mg / ml, even more preferably 22.5 ± 4 mg / ml, even more preferably 22.5 ± 3 mg / ml, most preferably 22.5 ± 2 mg / ml, and in particular 22.5 ± 1 mg / ml, based on the total volume of all aqueous phases within the composition.

In another preferred embodiment, the concentration of tapentadol is in the range of 25 ± 6 mg / ml, more preferably 25 ± 5 mg / ml, even more preferably 25 ± 4 mg / ml, even more preferably 25 ± 3 mg / ml, most preferably 25 ± 2 mg / ml, and in particular 25 ± 1 mg / ml based on the total volume of all aqueous phases within the composition.

- 6 025194

In another preferred embodiment, the concentration of tapentadol is in the range of 27.5 ± 6 mg / ml, more preferably 27.5 ± 5 mg / ml, even more preferably 27.5 ± 4 mg / ml, even further more preferably 27, 5 ± 3 mg / ml, most preferably 27.5 ± 2 mg / ml, and in particular 27.5 ± 1 mg / ml, based on the total volume of all aqueous phases within the composition.

In yet another preferred embodiment, the concentration of tapentadol is in the range of 30 ± 6 mg / ml, more preferably 30 ± 5 mg / ml, even more preferably 30 ± 4 mg / ml, even more preferably 30 ± 3 mg / ml, most preferably 30 ± 2 mg / ml, and in particular 30 ± 1 mg / ml, based on the total volume of all aqueous phases within the composition.

In yet another preferred embodiment, the concentration of tapentadol is in the range of 32.5 ± 6 mg / ml, more preferably 32.5 ± 5 mg / ml, even more preferably 32.5 ± 4 mg / ml, even further more preferably 32 5 ± 3 mg / ml, most preferably 32.5 ± 2 mg / ml, and in particular 32.5 ± 1 mg / ml, based on the total volume of all aqueous phases within the composition.

In yet another preferred embodiment, the concentration of tapentadol is in the range of 35 ± 6 mg / ml, more preferably 35 ± 5 mg / ml, even more preferably 35 ± 4 mg / ml, even more preferably 35 ± 3 mg / ml most preferably 35 ± 2 mg / ml, and in particular 35 ± 1 mg / ml based on the total volume of all aqueous phases within the composition.

In a preferred embodiment, the composition does not contain any preservative. For purposes of description, a preservative preferably refers to any substance that is usually added to pharmaceutical compositions in order to protect them from microbial degradation or the growth of microbes. In this regard, microbial growth traditionally plays a significant role, i.e. a preservative serves the main purpose of preventing microbial contamination. As a concomitant aspect, it may also be desirable to prevent any activity of microbes on active substances and excipients, respectively, i.e. prevent microbial degradation.

Typical examples of preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylene, cresol, phenoxyethyl, phenylethylene, phenethyl, phenol ethylene, hexene alcohol, phenyl mercury nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid, and potassium sorbate.

The complete absence of preservatives in the composition is preferred when the content of tapentadol is high enough so that, due to its properties, the desired shelf life or stability during use can be achieved by the presence of the drug itself. Preferably, under these conditions, the concentration of tapentadol is at least 10 mg / ml, at least 12.5 mg / ml, at least 15 mg / ml, or at least 17.5 mg / ml based on the total volume of the aqueous phase.

For the purpose of description, it is preferable to distinguish between shelf life and stability during use. Shelf life preferably refers to stability during storage of a closed container of the pharmaceutical composition. Stability during use preferably refers to a storage container that contains a multi-use preparation that was first used. Traditionally, the shelf life of the drug for repeated use is much longer than its stability during use.

In another preferred embodiment, the composition further comprises a preservative, which is preferably selected from the group consisting of benzalkonium chloride, benzetonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylene, cresol ethyl alcohol, glycerol, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercury nitrate, propylene glycol, sodium propionate, thimerosal, meth lparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, sorbic acid, and also potassium sorbate.

Surprisingly, it was found that water-based tapentadol compositions containing sodium benzoate showed a lower overall decomposition of products compared to water-based tapentadol compositions containing parabens.

Thus, sodium benzoate is a particularly preferred preservative in accordance with the invention.

Preferably, the preservative is contained in such an amount that in the absence of tapentadol it will not be sufficient to preserve the pharmaceutical composition in accordance with the European Pharmacopoeia.

Preferably, the preservative content is not more than 5.0 wt.%, More preferably

- 7 025194 not more than 4.0 wt.%, Even more preferably not more than 3.0 wt.%, Even further more preferably not more than 2.0 wt.%, Most preferably not more than 1.0 wt.%, In particular not more than 0.5 or not more than 0.2 wt.%, based on the total weight of the aqueous phase.

It was found that the antimicrobial effect of tapentadol, its preservative effect, depends on the pH value. Thus, at a given pH value, a certain minimum concentration of tapentadol is already sufficient to achieve the desired preservative effect, while at a different pH value, another minimum concentration of tapentadol is necessary in order to achieve the same preservative effect. The indicated minimum concentration for a given pH value can be determined using routine experiments.

In a preferred embodiment, the preservative, preferably benzoic acid or its sodium salt, has a concentration within the range of 1.0 ± 0.6 mg / ml, more preferably 1.0 ± 0.5 mg / ml, even more preferably 1, 0 ± 0.4 mg / ml, still further more preferably 1.0 ± 0.3 mg / ml, most preferably 1.0 ± 0.2 mg / ml, and in particular 1.0 ± 0.1 mg / ml based on the total volume of the aqueous phase.

In another preferred embodiment, the preservative, preferably benzoic acid or its sodium salt, has a concentration within the range of 1.5 ± 0.6 mg / ml, more preferably 1.5 ± 0.5 mg / ml, even more preferably 1 5 ± 0.4 mg / ml, even further more preferably 1.5 ± 0.3 mg / ml, most preferably 1.5 ± 0.2 mg / ml, and in particular 1.5 ± 0, 1 mg / ml, based on the total volume of the aqueous phase.

In yet another preferred embodiment, the preservative, preferably benzoic acid or its sodium salt, has a concentration within the range of 2.0 ± 0.6 mg / ml, more preferably 2.0 ± 0.5 mg / ml, even more preferably 2.0 ± 0.4 mg / ml, still further more preferably 2.0 ± 0.3 mg / ml, most preferably 2.0 ± 0.2 mg / ml, and in particular 2.0 ± 0 , 1 mg / ml, based on the total volume of the aqueous phase.

In yet another preferred embodiment, the preservative, preferably benzoic acid or its sodium salt, has a concentration within the range of 2.5 ± 0.6 mg / ml, more preferably 2.5 ± 0.5 mg / ml, even more preferably 2.5 ± 0.4 mg / ml, even further more preferably 2.5 ± 0.3 mg / ml, most preferably 2.5 ± 0.2 mg / ml, and in particular 2.5 ± 0.1 mg / ml, based on the total volume of the aqueous phase.

The additional presence of a preservative in the composition is preferred when the content of tapentadol is quite low, so that due to its preservative properties, the desired shelf life or stability during use cannot be achieved by the presence of the drug on its own. As mentioned above, the preservative property of tapentadol depends on the pH value and, therefore, at one pH value, the addition of another preservative should be necessary, while at a different pH value, it can be completely abandoned. Preferably, under these conditions, the concentration of tapentadol is not more than 12.5, not more than 10, not more than 8.0, not more than 7.5, not more than 5.0, not more than 4.0, not more than 3.0 or not more than 2 , 5 mg / ml based on the total volume of the aqueous phase.

In a preferred embodiment, the relative weight ratio of tapentadol to preservative is in the range from 10: 1 to 0.25: 1, more preferably 9: 1-0.33: 1, even more preferably 8: 1-0.5: 1, more further more preferably 7: 1-0.66: 1, most preferably 6: 1-0.75: 1, in particular 5: 1-1: 1. Preferably, the relative weight ratio of tapentadol to preservative is in the range of 5: 1 to 1: 1, more preferably 4.5: 1-1: 1, even more preferably 4: 1-1: 1, even further more preferably 3.5: 1- 1: 1, most preferably 3: 1-1: 1, in particular 2.5: 1-1: 1.

Preferably, the sum of the concentration of tapentadol and the concentration of preservative is below 30 mg / ml based on the total volume of the aqueous phase.

In a preferred embodiment, the sum of the concentration of tapentadol and the concentration of preservative is in the range of 20 ± 15 mg / ml, more preferably 20 ± 17.5 mg / ml, even more preferably 20 ± 15 mg / ml, even more preferably 20 ± 10 mg / ml, most preferably 20 ± 7.5 mg / ml, and in particular 20 ± 5 mg / ml based on the total volume of the aqueous phase.

In another preferred embodiment, the sum of the concentration of tapentadol and the concentration of preservative is in the range of 15 ± 12.5 mg / ml, more preferably 15 ± 10 mg / ml, even more preferably 15 ± 7.5 mg / ml, even further more preferably 15 ± 5 mg / ml, and most preferably 15 ± 3 mg / ml, and in particular 10 ± 1 mg / ml based on the total volume of the aqueous phase.

In yet another preferred embodiment, the sum of the concentration of tapentadol and the concentration of preservative is in the range of 10 ± 8 mg / ml, more preferably 10 ± 6 mg / ml, even more preferably 10 ± 4 mg / ml, even more preferably 10 ± 3 mg / ml

- 8 025194 most preferably 10 ± 2 mg / ml, and in particular 10 ± 1 mg / ml based on the total volume of the aqueous phase.

In a preferred embodiment, the preservative content is not more than 90%, more preferably not more than 80%, even more preferably not more than 70%, even further more preferably not more than 60%, most preferably not more than 50%, in particular not more than 40% of the content which is required by the European Pharmacopoeia. In order to preserve the pharmaceutical composition in the absence of tapentadol, they either care about its shelf life or, in the case of preparations for repeated use, do not necessarily care about their stability during use. The criteria for sufficient conservation in accordance with the European Pharmacopoeia are met if (a) the concentration of viable bacteria is reduced by no more than 0.1% of the initial concentration on the fourteenth day; and (b) the concentration of each test microorganism remains at or below the specified levels during the remaining 28-day test time. The specified criteria, in particular, are defined in the experimental section. Preferably, after 2 days, a logarithmic decrease of 2 times is achieved, after 7 days, a logarithmic decrease of 3 times is achieved, and in the future there may be no increase.

Preferably, the composition of the invention exhibits antimicrobial resistance that meets the requirements of the European Pharmacopoeia, preferably its 2010 version. Preferably, antimicrobial resistance is achieved against E. soy, 8. aiteic, Pk. Aegidshock, 8. krr. C. aYsaik, and / or A. where, the requirement of a logarithmic reduction of 1, preferably 3 times after 14 days and no increase after 28 days, is preferably satisfied. In a particularly preferred embodiment, antimicrobial resistance against bacteria is achieved while satisfying the requirement of a logarithmic reduction of 3 times after 14 days, and antimicrobial resistance against mold fungi and yeast, where the logarithmic reduction is 1 time after 14 days.

Preferably, the composition in accordance with the invention exhibits shelf life under accelerated aging, which is at least 1 month, more preferably at least 2 months, even more preferably at least 3 months, even further more preferably at least 4 months, most preferably at least 5 months, in particular at least 6 months. Preferably, the shelf life is determined in accordance with the European Pharmacopoeia, in particular, as described in the experimental section. Accelerated aging conditions preferably mean 40 ± 2 ° C / 75% RH.

Preferably, the composition according to the invention exhibits an shelf life of at least 6 months, more preferably at least 12 months, even more preferably at least 15 months, even further more preferably at least 18 months, most preferably at least 21 months, in particular at least 24 months.

Preferably, the composition according to the invention is a multi-use preparation that exhibits resistance during use under environmental conditions that is at least 1 week, more preferably at least 2 weeks, even more preferably at least 3 weeks, still further more preferably at least 4 weeks, most preferably at least 5 weeks, in particular at least 6 weeks.

Preferably, the composition according to the invention further comprises at least one lipid.

In a preferred embodiment, the composition comprises one lipid.

In another preferred embodiment, the composition comprises a mixture of at least two lipids.

In a preferred embodiment, the lipid is selected from the group consisting of saturated C ₈ -C ₄₈ fatty acids, such as myristic acid and stearic acid; unsaturated C ₈ -C _{] 8} fatty acids and their esters, such as oleic acid and ethyl oleate;

mixtures of saturated and unsaturated C ₈ -C ₈ fatty acids, which include vegetable oils such as soybean oil and peanut butter; hydrogenated oils, such as hydrogenated castor oil; and animal fats; and glycerides of fatty acids, which include monoglycerides, diglycerides, triglycerides, as well as mixtures thereof; preferably C ₆ -C ₂ fatty acids, more preferably C ₆ -C ₁₀ fatty acids, such as mixtures of caprylic / capric triglycerides, most preferably medium chain triglycerides according to the European Pharmacopoeia or the US Pharmacopoeia, for example, known and commercially available under trade names Сар1ех® and Мтд1уо1®;

fatty acid propylene glycol esters such as propylene glycol monocaprylate

- 9,025,194 (known and commercially available under the trade name Sarguo1®);

waxes, which include wool wax, carnauba wax, beeswax, and mixtures of saturated C18-C32 hydrocarbons such as hard paraffin and soft paraffin (for example, white petrolatum).

Preferably, the lipid is a mono alcohol C ₈ -C ₁₈ fatty acid ester (e.g. C ₁ -C ₁₂ alkyl alcohols), a di-C ₈ -C ₁₈ fatty acid ester of a alcohol (e.g. ethylene glycol or propylene glycol) or ester tri-C ₈ -C ₁₈ fatty acid of a trialcohol (e.g. glycerin).

Particularly preferred are medium chain triglycerides according to the European Pharmacopoeia or the US Pharmacopoeia, such as said caprylic / capric triglyceride mixtures.

Preferably, the lipid content in the composition is in the range from 0.1 to 90 wt.%, Preferably from 1 to 80 wt.%, More preferably from 5 to 70 wt.%, Even more preferably from 10 to 50 wt.%, Still further more preferably from 15 to 45 wt.%, and also most preferably from 20 to 40 wt.% based on the content of all lipids contained in the composition.

In a preferred embodiment, the lipid is semi-solid or solid at room temperature; those. lipid is wax or solid fat.

Preferably, the semi-solid or solid lipid has a melting point which is at most 100 ° C, more preferably which is at most 95 ° C, even more preferably which is at most 90 ° C, and also most preferably which is at most 85 ° C, even more preferably, which is at most 80 ° C, and also most preferably, which is at most 75 ° C.

In another preferred embodiment, the lipid is liquid at room temperature; those. lipid is an oil.

Preferably, the oil has a density within the range of 0.94 ± 0.07 g / cm ³ , more preferably 0.94 ± 0.06 g / cm ³ , even more preferably 0.94 ± 0.05 g / cm ³ still further more preferably 0.94 ± 0.04 g / cm ³ , even more preferably 0.94 ± 0.03 g / cm ³ , most preferably 0.94 ± 0.02 g / cm ³ , and also, in particular , 0.94 ± 0.01 g / cm ³ .

Preferably, the pure oil has a viscosity at a temperature of 20 ° C. established in accordance with European Pharmacopoeia 2.2.8, within a range of 30 ± 9 MPa-s, more preferably 30 ± 8 MPa-s, even more preferably 30 ± 7 MPa s, still further more preferably 30 ± 6 MPa-s, even more preferably 30 ± 5 MPa-s, most preferably 30 ± 4 MPa-s, and in particular 30 ± 3 MPa-s.

In a particularly preferred embodiment, the composition comprises both oil and wax. For example, the composition may contain a mixture of liquid triglyceride and soft paraffin.

Preferably, the relative weight to oil to wax ratio is in the range from 30: 1 to 1:30, more preferably 20: 1-1: 20, even more preferably 10: 1-1: 15, even further more preferably 5: 1-1: 10, most preferably 1: 1-1: 7.5, in particular 1: 2-1: 5.

Preferably, the composition according to the invention further comprises a surfactant.

A surfactant may act as an emulsifying agent, wetting agent, solubilizer and / or detergent.

In a preferred embodiment, the surfactant acts as an oil-water emulsifying agent. In another preferred embodiment, the surfactant acts as a water-oil emulsifier.

In a preferred embodiment, the composition comprises one surfactant. In another preferred embodiment, the composition comprises a mixture of two or more surfactants.

Preferably, the surfactants contained in the composition have a weighted average HLB value (hydrophilic-lipophilic balance), which is at least 10, in particular, the HLB value is between 11 and 14.

The surfactant may be an ionic surfactant, an amphoteric surfactant, or a nonionic surfactant.

In a preferred embodiment, the surfactant is ionic, in particular anionic. Suitable anionic ionic surfactants include, but are not limited to, sodium lauryl sulfate (sodium dodecyl sulfate), sodium cetyl stearyl sulfate, sodium dioctyl sulfosuccinate (sodium docusate); and their corresponding potassium or calcium salts.

In another preferred embodiment, the surfactant is cationic. Suitable cationic ionic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzetonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cetyltrimethylammonium chloride, 5-bromo-5-nitro1,3-dioxamide and dimethanedio dimethyldioctadecylammonium bromide; and halogen- 10 025194 hydrogen amine salts such as octenidine dihydrochloride

In yet another preferred embodiment, the surfactant is amphoteric. Suitable amphoteric surfactants include a group of phospholipids, for example lecithin.

In yet another preferred embodiment, the surfactant is non-ionic. Suitable non-ionic surfactants include, but are not limited to, polyoxyethylene esters of sorbitol and fatty acids, for example mono-trilauryl, palmityl, stearyl and oleyl esters, such as the type known as polysorbate and commercially available under the trade name T \ usp ®. including surfactants Kusp 20 [polyoxyethylene (20) sorbitan monolaurate], Kusp 40 [polyoxyethylene (20) sorbitan monopalmitate], 60 [polyoxyethylene (20) sorbitan monostearate], Kusp 65 [polyoxyethylene (20) sorbitan tristearate], Kusp 80 [polyoxyethylene (20) sorbitan monooleate], Kusp 85 [polyoxyethylene (20) sorbitan trioleate], Kusp 21 [polyoxyethylene (4) sorbitan monolaurate] and Kusp 81 [polyoxyethylene (5) sorbitan monooleate];

glycerol fatty acid polyoxyethylene esters, for example mono- and trilauryl, palmityl, stearyl and oleyl esters, such as the type known and commercially available under the trade name Tada! ®;

polyoxyethylene fatty acid esters, where the fatty acid preferably has from about 8 to about 18 carbon atoms, such as diglycol stearate, glycol stearate, glycol distearate and mixtures of 12-hydroxystearic acid polyoxyethylene esters, such as a type known and commercially available under the trade the name 8o1i! o1®;

polyoxyethylene esters of alpha-tocopheryl succinate, for example Ό-alpha-tocopherylPEG-1000-succinate (TPO8);

polyglycolized glycerides, such as types known and commercially available under the trade names Oe1is1ge® and LaBa8a1®;

reaction products of natural or hydrogenated castor oil and ethylene oxide, such as various liquid surfactants known and commercially available under the trade name Szetoryog®;

fatty acid glycerol esters, for example mono- and trilauryl, palmityl, stearyl and oleyl esters, including diglycol stearate, glycerol monostearate, glycerol monopalmitate and glycerol trioleate;

fatty alcohols or sterols, including cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol and cholesterol.

In a particularly preferred embodiment, the pharmaceutical composition according to the invention comprises a surfactant or a mixture of various surfactants which can be obtained by esterifying saturated or unsaturated C ₁₂ -C ₁₈ fatty acids, optionally having a hydroxyl group, glycerol and optionally polyethylene glycol; moreover, the polyethylene glycol preferably contains 10-40 ethylene oxide units (—CH ₂ CH ₂ O—).

Particularly preferred surfactants that are contained in the composition according to the invention are nonionic surfactants having a hydrophilic lipophilic balance (HLB) of at least 10, in particular nonionic surfactants of importance An HLB of at least 12, more specifically nonionic surfactants having an HLB value of between 14 and 16. Examples of this type of surfactant are the surface-active substances Tueyep® 80, 8o1i! o1® H8 15 and Tada! ® 82.

In another preferred embodiment, the pharmaceutical composition according to the invention comprises at least one surfactant having an HLB value of at least 10 (hydrophilic surfactant) and at least one surfactant, having an HLB value below 10 (lipophilic surfactant). For example, the composition may contain macrogol-20 glycerol hydroxide stearate 40 (e.g. Tada! ® 82) and / or cetyl alcohol as the hydrophilic component of the surfactant and glycerol monostearate as the lipophilic component of the surfactant.

Preferably, the hydrophilic surfactant is selected from the group consisting of macrohydroxystearate, macrogolglyceryl hydroxystearate and macrogolglyceryl laurate, wherein the macrogol portion preferably contains 15-45 ethylene oxide units; and / or a group consisting of cetyl alcohol, stearyl alcohol and cetyl stearyl alcohol.

Preferably, the lipophilic surfactant is selected from the group consisting of glycerol monostearate, glycerol monopalmitate, and glycerol trioleate.

- 11 025194

Preferably, the relative weight ratio of a surfactant having an HLB value of at least 10 (hydrophilic surfactant) and a surfactant having an HLB value of less than 10 (lipophilic surfactant) is greater than or equal to 1.

Preferably, the relative weight ratio of a surfactant having an HLB value of at least 10 (hydrophilic surfactant) and a surfactant having an HLB value below 10 (lipophilic surfactant) is in the range of 20: 1- 1:15, more preferably 15: 1-1: 10, even more preferably 12: 1-1: 8, even further more preferably 10: 1-1: 6, even more preferably 7: 1-1: 5, most preferably 5: 1-1: 2, in particular 4: 1-1: 1.

In a preferred embodiment, the surfactant content is at least 0.1 wt.%, More preferably at least 1 wt.%, Even more preferably at least 2 wt.%, Or at least 3 wt.%, even further more preferably at least 5 wt.%, or at least 7 wt.%, most preferably at least 10 wt.%, or at least 12 wt.%, and in particular at least 14 wt.% or at least 15 wt.% based on the total weight of the composition.

In a preferred embodiment, the surfactant content ranges preferably from 0.1 to 95 wt.%, More preferably from 1 to 80 wt.%, Even more preferably from 2.5 to 70 wt.%, Even further more preferably from 5 up to 50 wt.%, most preferably from 7.5 to 30 wt.%, and also, in particular, from 10 to 25 wt.% based on the total weight of the composition.

In a preferred embodiment, the relative ratio of the mass of the surfactant to the mass of the lipid is in the range from 20: 1 to 1:20, more preferably in the range of 10: 1-1: 10, even more preferably 7.5: 1-1: 5, still further more preferably 6: 11: 2, most preferably within the range of 5: 1-1: 1, in particular 3.5: 1-1.5: 1.

The composition in accordance with the invention may further comprise a hydrophilic solvent.

The hydrophilic solvent may be selected from the group consisting of propylene glycol, ethanol, poly (ethylene glycol) or PEG, propylene carbonate, diethylene glycol monoethyl ether, poloxamer, glycofurol, glycerol, as well as mixtures thereof.

The composition in accordance with the invention may be buffered, i.e. contain one or more buffer solutions and buffer systems (i.e., acid-base conjugated pairs), respectively. Preferred buffer systems are derived from the following acids: organic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malonic acid, malic acid, mandelic acid, citric acid, tartaric acid; or inorganic acids, such as phosphoric acid, or organic bases, such as trometamol.

Buffer systems derived from citric acid, phosphoric acid or trometamol are particularly preferred. When buffer systems are prepared from any of the above acids, the buffer system consists of the specified acid and its conjugate base.

The skilled person is well aware that multiprotonic acids can form more than one buffer system. For example, citric acid is a three-protic acid such that it forms acid-base conjugated pairs such as citric acid-dihydrogen citrate, dihydrogen citrate-hydrogen citrate and hydrogen citrate-citrate. In other words, any of citric acid, dihydrogen citrate and hydrogen citrate may be an acid of a conjugated base buffer system. For the purpose of description, the expression buffer solution and buffer system, respectively, preferably refers to the amount of both, an acid and its conjugate base. In addition, one skilled in the art is well aware that a buffer system, for example a conjugated citric acid / sodium dihydrogen citrate system, can be established either by adding citric acid and an appropriate amount of sodium hydroxide, or citric acid and sodium dihydrogen citrate per se.

Liquid and semi-solid compositions may differ in their viscosity and fluidity and are classified as follows.

Newtonian fluids exhibit ideal flow characteristics; those. the relationship between shear stress and shear rate is linear and their viscosity is thus independent of shear rate. Pure liquids usually exhibit Newtonian fluid characteristics.

The most semi-solid compositions, however, show a non-linear relationship between shear stress and shear rate. They are referred to as non-Newtonian fluids or structurally viscous fluids. In accordance with their different relationships between shear stress and shear rate, they are classified as a pseudo-plastic, dilatant fluid, Bingham plastic body or Kasson plastic body.

Pseudoplastic fluids exhibit a decreasing viscosity as the applied shear rate is increased. Examples are creams that contain asymmetric solids.

Dilatant fluids exhibit increasing viscosity as the applied shear rate is increased. Examples of this type are pastes having a high solids content.

Plastic fluids are not able to flow at low shear stresses. However, after a certain value of the shear stress, the so-called shear yield strength is reached, and they can show ideal plastic fluidity (Bingham plastic fluid) or non-ideal fluidity (Casson plastic fluid). Examples are gels in which a polymer structure formed by a gelling agent will be destroyed by a certain amount of shear stress before fluidity can occur. After the structure has been destroyed and the shear stress is further increased, the liquid can, for example, behave like a liquid medium and demonstrate Newtonian characteristics. After the shear stress is removed, the fluid usually regains its plastic flow characteristics, most often, however, with a time lag (thixotropic fluid).

Fluids may also exhibit a combination of the aforementioned flow characteristics. For example, a fluid may exhibit behavior as a Newtonian fluid at low shear stresses and behavior as a pseudoplastic fluid at high shear stresses.

The viscosity and fluidity of a liquid or semi-solid composition can be determined empirically using a rotational viscometer.

Preferably, the composition according to the invention exhibits a viscosity of at most 10 ¹² mPa-s, more preferably at most 10 ¹⁰ mPa-s, even more preferably at most 10 ⁹ mPa-s, still further more preferably at most 10 ⁸ MPa-s, most preferably constituting the largest 10 ⁷ MPa-s, and also, in particular, a component of 10 ⁶ MPa-s. In a preferred embodiment, the viscosity is in the range from 1 to 100 Pa-s, more preferably 5-20 Pa-s, established in accordance with the European Pharmacopoeia.

In a preferred embodiment, the composition in accordance with the invention demonstrates the characteristics of a Newtonian fluid.

In another preferred embodiment, the composition exhibits non-Newtonian fluid characteristics.

Preferably, the semi-solid composition is selected from the group of pseudoplastic fluids, dilatant fluids and plastic fluids.

In a preferred embodiment, the semi-solid composition shows the flow characteristics of the dilatant fluid.

In another preferred embodiment, the semi-solid composition exhibits flow characteristics of a plastic fluid. The plastic fluid may be a Bingham plastic fluid or a Casson plastic fluid.

Preferably, the plastic fluid also exhibits viscoelastic properties.

In yet another preferred embodiment, the semi-solid composition exhibits flow characteristics of a pseudoplastic fluid.

Preferably, the viscosity curve of a pseudoplastic fluid is similar to the viscosity curve of a Newtonian fluid at low shear stresses and / or at high shear stresses.

Preferably, at low shear stresses, which are at most 50 Pa, and at 25 ° C., the viscosity does not change by more than 40%, more preferably not more than 30%, even more preferably not more than 20%, most preferably no more than 10%.

Preferably, at low shear stresses, which is at most 100 Pa, and at 25 ° C., the viscosity does not change by more than 40%, more preferably not more than 30%, even more preferably not more than 20%, most preferably no more than 10%.

Preferably, at a shear rate of 40 s − ¹ and at 25 ° C., the composition exhibits a viscosity within the range of 1 MPa-s to 1-10 ¹² MPa s, more preferably within the range of 2 MPa s to 1 10 ¹¹ MPa s, even more preferably within the range of 5 MPa s to 1 10 ¹⁰ MPa s, even further more preferably within the range of 10 MPa s to 1 10 ⁹ MPa s, most preferably within the range constituting from 50 MPa s to 1 10 ⁶ MPa s, and also, in particular, within a range of 10 ² MPa s to 1 10 ⁴ MPa s.

Preferably, at a shear rate of 80 s ⁻¹ and at 25 ° C., the composition exhibits a viscosity within the range of 1 MPa-s to 1 10 ¹² MPa-s, more preferably within a range of 2 MPa-s up to 1 10 ¹¹ MPa-s, even more preferably within the range of 5 MPa-s to 1 10 ¹⁰ MPa-s, even further more preferably in the range of 10 MPa-s to 1 10 ⁹ MPa-s, most preferably within the range of 50 MPa-s to 1 10 ⁶ MPa-s, and also, in particular, in in the range of 10 ² MPa-s to 1 10 ⁴ MPa-s.

Preferably, at a shear rate of 120 s ⁻¹ and at 25 ° C., the composition exhibits viscosity within a range of 1 MPa-s to 1 10 ¹² MPa-s, more preferably within a range of 2 MPa-s up to 1 10 ¹¹ mPa-s, even more preferably within the range of 5 MPa-s to 1 10 ¹⁰ MPa-s, even more preferably within the range of 10 MPa-s to 1 10 ⁹ MPa-s most preferably within the range of from 50 mPa-s to 1 June ¹⁰ mPa-s, and in particular to limit range is from 10 ² mPa-s to 1 April ¹⁰ mPa-s.

Preferably, at a shear rate of 160 s ⁻¹ and at 25 ° C., the composition exhibits viscosity within a range of 1 MPa-s to 1 10 ¹² MPa-s, more preferably within a range of 2 MPa-s up to 1 10 ¹¹ mPa-s, even more preferably within the range of 5 MPa-s to 1 10 ¹⁰ MPa-s, even more preferably within the range of 10 MPa-s to 1 10 ⁹ MPa-s most preferably within the range of from 50 mPa-s to 1 June ¹⁰ mPa-s, and in particular to limit range is from 10 ² mPa-s to 1 April ¹⁰ mPa-s.

In a preferred embodiment, at a shear rate of 40 s ⁻¹ and at 25 ° C., the composition exhibits a viscosity of preferably at least 4.850 mPa-s, more preferably at least 4.900 mPa-s, even more preferably at at least 4,950 mPa-s, even more preferably a component of at least 5,000 mPa-s, most preferably a component of at least 5,100 mPa-s, and in particular a component of at least 5,200 mPa-s.

In a preferred embodiment, at a shear rate of 80 s ⁻¹ and at 25 ° C., the composition preferably exhibits a viscosity of at least 2,250 mPa-s, more preferably at least 2,300 mPa-s, even more preferably at at least 2,350 mPa-s, even more preferably at least 2,400 mPa-s, most preferably at least 2,450 mPa-s, and in particular at least 2,500 mPa-s.

In a preferred embodiment, at a shear rate of 120 s ⁻¹ and at 25 ° C., the composition exhibits a viscosity, preferably at least 1,600 mPa-s, more preferably at least 1,650 mPa-s, even more preferably at at least 1,700 mPa-s, even more preferably at least 1,750 mPa-s, most preferably at least 1,800 mPa-s, and in particular at least 1,850 mPa-s.

In a preferred embodiment, at a shear rate of 160 s ⁻¹ and at 25 ° C., the composition exhibits a viscosity, preferably at least 1,300 mPa-s, more preferably at least 1,350 mPa-s, even more preferably at at least 1,400 mPa-s, even further more preferably a component of at least 1,450 mPa-s, and also most preferably a component of at least 1,500 mPa-s.

The composition in accordance with the invention may be transparent, translucent or opaque.

In a preferred embodiment, the composition is translucent, having a visible light transmission that is at least 10%, more preferably at least 20%, even more preferably at least 30%, even further more preferably at least 50% , even more preferably at least 70%, most preferably at least 80%, and in particular at least 90%.

In a preferred embodiment, the composition is translucent, having a transmittance of visible light that is at least 90%, more preferably at most 80%, even more preferably at most 70%, even more preferably at most 50%, even more preferably constituting at most 30%, most preferably constituting at most 20%, and also, in particular, constituting at most 10%.

The compositions may include one or more additional excipients selected from the group consisting of thickening agents, gelling agents, antioxidants, flavoring agents, chelating agents, and penetration promoting agents.

A thickening agent, a viscosity enhancing agent, or a gelling agent can typically be included in order to thicken the liquid composition. Given that any suitable

- 14,025,194 thickening agent may be included in the compositions of the present invention, a preferred thickening agent, if used, includes one or more of the following: gum arabic, alginic acid, bentonite, calcium or sodium carboxymethyl cellulose, cetostearyl alcohol, methyl cellulose, ethyl cellulose, glycerin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, locust bean gum, maltodextrin, pectin, polyacrylic acid and its derivatives ( rbomery), polyvinyl alcohol, polyvinylpyrrolidone, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch, highly dispersed silicon dioxide, tragacanth gum, tragacanth and xanthan gum, and any combination thereof. More preferred thickening agents are carbomer, cellulose derivatives such as sodium carboxymethyl cellulose and methyl cellulose, galactomannans such as guar gum and locust bean gum, sodium alginate, and any combination thereof. Such a thickening agent, if present, traditionally comprises about 0.1-20 wt.%, Preferably about 0.3-about 15 wt.%, And also more preferably about 0.5-4 wt.% Of the total weight of the composition.

Examples of a suitable antioxidant component, if used, include one or more of the following: sulfites; ascorbic acid; ascorbates, such as sodium ascorbate, calcium ascorbate, or potassium ascorbate; ascorbyl palmitate; fumaric acid; ethylenediaminetetraacetic acid (EDTA) or its sodium or calcium salts; tocopherol; gallates such as propyl gallate, octyl gallate, or dodecyl gallate; Vitamin E butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), as well as mixtures thereof. Adding an antioxidant component can help increase and guarantee the stability of the composition and ensure the stability of the composition even after six months at a temperature of 40 ° C. A suitable amount of the antioxidant component, if present, is about 0.01 to about 3 wt.%, Preferably about 0.05 to about 2 wt.% Of the total weight of the composition.

The composition in accordance with the invention may further comprise a flavoring agent. Suitable flavoring agents include lavender oil, rose oil, lemon oil and almond oil.

Examples of a suitable chelating agent, if used, include citric acid, maleic acid and ethylenediaminetetraacetic acid (EDTA) and its sodium or calcium salts.

The composition in accordance with the invention may contain a penetration enhancing substance that improves transdermal drug delivery. Suitable penetration aids include cyclodextrins, ethanol, oleic acid, lecithin, propylene glycol, propylene glycol fatty acid esters (e.g. propylene glycol dipelargonate), polyethylene glycol, as well as terpenes such as nerolidol, geraniol, carvacrol, lemon, eva linalool and cineole.

Preferably, the pharmaceutical composition is intended for the treatment of acute or chronic pain.

In a preferred embodiment, the pain refers to wounds, burns, ulcers or boils of the skin and / or mucous membranes.

In another preferred embodiment, the pain refers to bone damage, joint damage and / or muscle damage.

Preferably, the pain refers to rheumatic fever, arthritis, joint pain, postoperative complaints, dental surgery, skin inflammation (dermatitis), skin lesions, skin cancer, oral ulcers and / or sports injuries.

In a preferred embodiment, the use of the composition is topically and / or locally. In this regard, local and / or local application includes any application of the composition to a site that is identical to the site of pain and / or at least adjacent. In particular, local and / or local application aims to deliver tapentadol directly to the desired site of exposure, thereby preventing systemic side effects.

Preferably, the systemic concentration of tapentadol is maintained at a subtherapeutic concentration; those. during treatment, the systemic concentration of tapentadol never reaches the level that is necessary for the manifestation of a therapeutic effect when the drug is used only systemically.

The composition can be applied topically to the skin, cornea of the eye, rectal tissue, nasal mucosa, vagina, buccal tissues, urethral mucosa and / or to the lining of the outer ear.

In another preferred embodiment, the use of the composition is intended to elicit a systemic mechanism of action.

Preferably, the composition in accordance with the invention is adapted for use once a day, twice a day, three times a day, four times a day, five times a day, six times a day, or even

- 15,025,194 more often.

In a preferred embodiment, the composition in accordance with the invention is adapted for use by pediatric, geriatric and / or pregnant patients.

For purposes of description, pediatric patients preferably include young children, children, as well as adolescents. Preferably, the upper age limit of such patients is 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21.

For the purposes of description, geriatric patients preferably include patients with a lower age limit of 60, preferably 62, more preferably 64, even more preferably 66, even further more preferably 68, and in particular 70.

In this regard, the unexpected preservative properties of tapentadol are even more beneficial, as the drug approval authority has recommended stricter standards regarding the presence of preservative in drugs for pediatric patients. In addition, since tapentadol is suitable for treating pain in patients suffering from serious diseases, for example for treating cancer pain, such patients, including pediatric patients, are usually treated simultaneously with other drugs, for example chemotherapeutic drugs, which have serious side effects. Under these conditions, it is even more desirable not to expose such pediatric patients to preservatives if this can be avoided.

In this regard, topical and / or local pain management is also beneficial, since the systemic concentration of tapentadol can be maintained at a subtherapeutic level, and systemic side effects that stress the entire body can be avoided. Maintaining the systemic concentration of the drug at a low level is especially critical in the treatment of, especially pediatric, geriatric and / or pregnant patients.

Preferably, the composition is a dosage form for repeated use, i.e. adapted for more than one application.

For the purposes of the description for repeated use, it preferably means that the composition comprises more than one dosage unit for single use.

For example, when the composition is a cream for repeated use, its entire volume is greater than the volume that is traditionally used at a time. Instead, the cream for repeated use is adapted so that it can be divided into many dosage units, which must be used during the treatment period, which is usually several days. For example, when the reusable composition that is contained in the storage container has a total volume of 20 ml and the prescribed dosage unit is approximately 2 ml once a day, on the 1st day of the treatment period, the patient takes 2 ml, thus , 18 ml remain in the storage container; on the 2nd day of the treatment period, the patient takes the next 2 ml, so 16 ml remains in the storage tank; and so on, until the patient takes the entire amount on the 10th day.

In a preferred embodiment, the water-based semi-solid composition according to the invention is ready to use, i.e. does not require separate processing steps, such as dispersion in a liquid medium, before it can be used by the patient.

One skilled in the art knows that a water-based semi-solid composition according to the invention, alternatively, can be put into mass production as a precursor in the form of a dry powder, which must be dispersed in an appropriate amount of water before its first use.

An additional aspect of the invention relates to a pharmaceutical dosage form containing a pharmaceutical composition in accordance with the invention. All preferred embodiments described above in connection with the composition of the invention also apply to the dosage form of the invention.

A still further aspect of the invention relates to the use of tapentadol for the manufacture of a pharmaceutical composition in accordance with the invention as described above, or a pharmaceutical dosage form in accordance with the invention as described above for the treatment of pain.

In a preferred embodiment, the composition is made by melting its semi-solid and / or solid ingredients, optionally in the presence of other ingredients, as well as mixing them with other ingredients until a homogeneous mixture is obtained.

In another preferred embodiment, the composition is prepared by separately preparing an aqueous phase comprising tapentadol, water, and preferably a surfactant; and a lipid phase containing a lipid, as well as optionally other ingredients, such as surfactants, waxes and / or lubricants;

and mixing the two phases thereafter, preferably at an elevated temperature at which both phases are liquid.

In yet another preferred embodiment, the composition is made by

- 16,025,194 grinding into powder of two or more ingredients.

In yet another preferred embodiment, the composition is made using ointment mixers.

Another additional aspect of the invention relates to a method for treating pain, comprising topical and / or local use of a pharmaceutical composition in accordance with the invention, as described above, or a pharmaceutical dosage form in accordance with the invention, as described above, for a patient who needs it.

In a particularly preferred embodiment, a composition is provided in accordance with the invention, wherein the content of tapentadol is in the range of 0.01-50% by weight; and / or where the water content is at least 0.5 wt.%; and / or which contains a surfactant having an HLB value of at least 10; and / or which contains a lipid, preferably a triglyceride; and / or which contains a wax selected from wool wax, carnauba wax, beeswax, hard paraffin, soft paraffin and white petroleum jelly;

which does not contain any preservative; and / or which is a biphasic or multiphase system containing at least one aqueous and at least one lipid phase, and the aqueous phase is preferably a coherent phase; and / or which is a non-Newtonian fluid; and / or which exhibits flow characteristics of a pseudoplastic fluid; and / or which is adapted for local and / or local use; and / or which is adapted for use by pediatric, geriatric and / or pregnant patients;

the manufacture of which involves the melting of semi-solid and / or solid ingredients.

Examples

The following examples further illustrate the invention, but should not be construed as limiting its scope.

Example 1

Creams were formulated in accordance with the following formulations.

Table 1

Ingredients (wt.%] S-1 1-1 Ι-2 Water phase Tapentadol HC1 0,0 0.6 1.25 Macrogol-20-glycerol-monostearate (Tada182) 7.0 7.0 7.0 Purified water 50,0 49.4 48.75 Lipid phase Glycerol monostearate 4.0 4.0 4.0 Cetyl alcohol 6.0 6.0 6.0 M1d1uo1® 812 7.5 7.5 7.5 White petroleum jelly 25.5 25.5 25.5

In creams, the aqueous phase represents a coherent phase (such as oil-water), so that the dosage form should in principle be sensitive to microbial contamination. Dosage forms were stored in yellow glass containers.

Assuming that tapentadol hydrochloride is present only in the aqueous phase, its concentration in it is 12.0 mg / ml (10.3 mg / ml tapentadol) for the dosage form in accordance with the invention 1-1 and 25.0 mg / ml ( 21.46 mg / ml tapentadol) for the dosage form in accordance with the invention 1-2.

§1arBy1ossossik aiteik (§1arN. Aiteik), Rkayyotoiak aetidshoka (Rk. Aetoidshoka), Akretdshik shdet (Akr. Shdet) and SapFya a1Ysaik and their antimicrobial protection efficacy were evaluated in accordance with European experience, Pharmacopoeial efficacy was evaluated according to European experience, and .

The criteria for the acceptability of experience for drugs in accordance with the European Pharmacopoeia are given in table. 2 and 3. Criteria A express the recommended effectiveness to be achieved. In justified cases where criteria A cannot be achieved, for example, due to an increased risk of an adverse reaction, criteria B must be met.

- 17 025194

table 2

Acceptance criteria for topical preparations (experience Antimicrobial efficacy, European Pharmacopoeia)

Experience criteria Logarithmic Reduction 2d 7d 14 d 28 d Bacteria BUT 2 3 - OP IN - - 3 OP Griby BUT - - 2 OP IN - - one OP

OP = No increase,

OB = no recovery.

Table 3

Acceptance criteria for parenteral preparations (experience Antimicrobial efficacy, European Pharmacopoeia)

Experience criteria Logarithmic Reduction 6 h 24 h 7D 14 d 28 d Bacteria BUT 2 3 - - OV IN - one 3 - OP Mushrooms BUT - - 2 - OP IN - one OP

OP = no increase,

OB = no recovery.

Experiments with the effectiveness of antimicrobial protection revealed that the placebo cream does not show any preservative effect of the dosage form as such. The antimicrobial effect of the dosage form containing tapentadol HC1 is, therefore, a consequence of the presence of tapentadol. Moreover, it has been demonstrated that the effectiveness of antimicrobial protection depends on the amount of tapentadol; however, the dosage form in accordance with the invention 1-1, containing 10.3 mg of tapentadol per 1 ml of the aqueous phase was protected with tapentadol to a certain extent, however, δΙαρΗ. Ageik (Crete. A and B) and Ark. where (crit. A) were not sufficiently reduced during the experiment in accordance with the parameters of the experiment. The dosage form in accordance with the invention 1-2 (21.6 mg of tapentadol per 1 ml of the aqueous phase), however, was sufficiently protected with tapentadol, even for all bacteria / fungi tested.

Conclusion

Experiments using different concentrations of tapentadol in the cream show that the concentration where the preservative effect of tapentadol begins begins lies between 12 and 25 mg of tapentadol HC1 in 100 ml of the aqueous phase. At an appropriate concentration, tapentadol can thus be used as a preservative for creams.

Example 2. The viscosity curves of the examples in accordance with the invention 1-1 and 1-2 were determined as follows.

The experiments were carried out using a Naake device Ko1oUyso KU1 (C60 / 1 ° sensor together with the OS30 temperature controller, Naake company) at 25.0 ± 0.1 ° С. Material (1.0 ml) was placed between the stator and the rotor and the gap between them was adjusted to 0.052 mm. The material was hardened at a temperature of 25.0 ° C before the start of the experiment. The viscosity curve was determined using LIEoXUT 3 software, and the viscosity values (n = 4) at different shear stresses (Δ = 40 s ⁻¹ ) were determined in order to characterize the samples in accordance with the invention.

The viscosity curve is shown in the drawing and the calculated viscosity values are shown in the following table.

Table 4

shear rate [1 / s] viscosity [MPa s] shear stress [Pa] one [from] AND Ι-2 1-1 Ι-2 1-1 Ι-2 40,000 4790.6 5457.8 191.59 218.26 161.80 122.39 80,000 2189.0 2722.7 175.11 217.80 197.81 158.39 120.00 1532.3 1917.9 183.87 230.14 233.81 194.39 160.00 1219.2 1533.4 195.07 245.34 269.79 230.38

In both cases, the viscosity decreases with increasing shear rate, i.e. both fluids exhibit pseudoplastic fluidity.

Example 3. The antimicrobial effect of tapentadol at pH 3 and 8.

A solution of tapentadol with a concentration of 15 mg / ml tapentadol (in the form of a free base) was prepared. The pH was adjusted to a predetermined value, which was 3 or 8, using citric acid and a 1 N NaOH solution, respectively. No additional buffer system was added. To ensure that the placebo solution alone does not show antimicrobial

- 18 025194 actions, a placebo solution was prepared with a pH of 8, with fixation at the same pH value, even if different amounts of a 1 N NaOH solution were used to adjust the pH.

Dosage forms were prepared, filled into glass bottles and autoclaved for 30 minutes at 121 ° C and 2 bar. In the sterilized glass bottles, δΐ ^ ρ ^ ΐο ^^^ aigeik (§1арЬ. Аигеик), Ркеиάотоη as aegidiyuk (Рк. Ае ^ ο ^ ^ ^ ο ка ка)), Akregd икik tdet (Acre. Ί ί ег))) and Caηά ά ά ά опыта experiment protection in accordance with monograph 5.1.3. European Pharmacopoeia 6.6.

The criteria for the acceptability of the experience of the European Pharmacopoeia for parenteral preparations are given in table. 1 (OD = no increase in OM = no recovery). Criteria A express the recommended effectiveness that should be achieved, in justified cases where criteria A cannot be achieved, for example, because of an increased risk of an adverse reaction, criteria B must be met. In order to reduce the number of experiments for this first series of experiments with pH value, control points after 6 and 24 hours were replaced by control points after 30 minutes (Table 5).

Table 5

Acceptance criteria for parenteral preparations for experience Antimicrobial efficacy (European Pharmacopoeia)

Logarithmic Reduction Experience criteria 6 h 24 h 7d 14d 28 d Bacteria BUT 2 3 - - OV IN - one 3 - OP Mushrooms BUT - - 2 - OP IN - - - one OP

The results of microbial testing of solutions are given for each bacteria / fungi in the table. 69.

Table 6

Microbial growth δΙ ^ ρΕ aigeik

Microbial number Placebo pH 8 Tapentadol pH 8 Tapentadol pH 3 Added bacteria / fungi 7.4 x 10 ⁵ 1.7x10® 1.6 x 10® 30 min 8.3 x 10® 8x 10® 2.5 x 10 ⁶ 7 days 2.8 x 10 ’ <x 10 ² 2.3 x 10 ³ 14 days did not check <x 10 ² <χ 10 ² 28 days did not check <x10 ² <x 10 ¹ Experience Criteria A not satisfies Satisfies Satisfies Test Criteria B not satisfies Satisfies Satisfies

Table 7

The growth of microbes Rk. aeg ^^ ka

Microbial number Placebo pH 8 Tapentadol pH 8 Tapentadol pH 3 Added bacteria / fungi 1.4x10® 1.7 x 10® 1.6 x 10® 30 min 1.6x10® / x1 σ ’ 4.5x10® 7 days 8.8 x 10® <x 10 ² ”2 x 10® 14 days did not check <x10 ² <x 10 ² 28 days did not check <χ 10 ² <χ 10 ² Experience Criteria A not satisfies Satisfies Satisfies Test Criteria B not satisfies Satisfies Satisfies

- 19 025194

Table 8

Microbial Growth Acre. where

Microbial number Placebo pH 8 Tapentadol pH 8 Tapentadol pH 3 Added bacteria / fungi 4.2 x 10 ⁵ 5.4 χ 10 ⁵ 3.9 χ 10 ⁵ 30 min 4.3 x 10 ⁵ 6 x 10 ^e 4.5 x 10 ^!> 7 days 6.3x10 ^b 4.5 x 10 ^ 8x 10 ⁴ 14 days did not check 0.3 χ 10 ^ζ 4.ΪΧ 10 ^b 28 days did not check 1.8x1 b ¹ 4.5x10 ^to Experience Criteria A not satisfies Satisfies Not satisfies Test Criteria B not satisfies Satisfies Not satisfies

Table 9

Microbial growth of SaiFba a1Ysaik

Microbial number Placebo pH 8 Tapentadol pH 8 Tapentadol pH 3 Added bacteria / fungi 2 χ 10 ⁵ 1.7 χ 10 ⁵ 2.4 x 10 ⁶ 30 min 2.5 χ 10 ⁵ <x10 ⁴ 2 x 10 ^minutes 7 days 3.4 x 10 ^s <x 10 ^ 1.3 x 10 ³ 14 days did not check <χ 10 ⁴ 1.8 x 10 ³ 28 days did not check <x 10 ^ 2.5 x ³ Experience Criteria A not satisfies Satisfies Not satisfies Test Criteria B not satisfies Satisfies Not satisfies

In the absence of additional preservatives, a solution of tapentadol with pH 3 is not sufficiently protected in accordance with the European Pharmacopoeia (Crete. A and B) for Acre. tdeg and saib. a1Ysaik, while a solution of tapentadol with a pH of 8 satisfies crit. A and B for all tested bacteria and fungi. A placebo solution with a pH of 8 does not show the preservative effect of the solution as such, so the antimicrobial effect of the dosage form containing tapentadol HC1 is a consequence of the added amount of tapentadol HC1. Taking into account these results, a clear dependence of the effect of pH on the preservative effect of tapentadol HC1 solution can be demonstrated.

A solution of tapentadol HC1 with a higher pH value of 8 has an improved antimicrobial effect compared to a solution with a pH value of 3, thus, a clear dependence of the effect of the pH value of the solution on the preservative effect of tapentadol was revealed.

Claims (14)

CLAIM 1. A semi-solid pharmaceutical composition based on water for topical and / or local use, containing tapentadol or a physiologically acceptable salt thereof, wherein the pH of the aqueous phase of the composition is at least 5.5. 2. A pharmaceutical composition according to any one of the preceding claims for the treatment of chronic or acute pain. 3. The pharmaceutical composition according to claim 2, where the pain refers to rheumatic fever, arthritic lesions, joint pain, postoperative complaints, dental surgery, skin inflammation (dermatitis), skin lesions, skin cancer, oral ulcers and / or to sports injuries. 4. The pharmaceutical composition in accordance with any of the preceding paragraphs, which is selected from the group consisting of ointments, creams, liquid ointments, gels, emulsions, suspensions, lotions, liniments, pastes, lotions, suspension gels and emulsion gels. 5. The pharmaceutical composition according to any one of the preceding claims, which is a biphasic dosage form or a multiphase dosage form. 6. The pharmaceutical composition in accordance with any of the preceding paragraphs, where the content of tapentadol is at least 0.55 wt.% Based on the total weight of the composition. 7. The pharmaceutical composition in accordance with any of the preceding paragraphs, which does not contain any preservative. 8. The pharmaceutical composition in accordance with any of the preceding paragraphs, additionally containing a preservative in an amount that in the absence of tapentadol will not be sufficient - 20 025194 for the protection of the pharmaceutical composition, in accordance with the European Pharmacopoeia. 9. The pharmaceutical composition in accordance with claim 8, where the preservative content is not more than 5.0 wt.% Based on the total weight of the composition. 10. The pharmaceutical composition according to any one of the preceding paragraphs, which further comprises a lipid and / or surfactant. 11. The pharmaceutical composition according to claim 10, wherein the lipid is selected from the group consisting of monoglycerides, diglycerides and triglycerides, as well as mixtures thereof. 12. The pharmaceutical composition according to claim 10 or 11, wherein the surfactant has an HLB value of at least 12. 13. The pharmaceutical composition according to any one of the preceding paragraphs, which shows the flow characteristics of a pseudoplastic fluid. 14. The pharmaceutical composition according to any one of the preceding paragraphs, which demonstrates shelf life under accelerated aging, which is at least 3 months.